Opiate-induced hyperalgesia has been reported in humans and in animals. Continuous opiate administration for several days produces pronociceptive neuroplastic adaptations in both the peripheral and central nervous systems which likely underlie the observed hypersensitivity. Despite the potential clinical significance of such changes, specific mechanisms of opiate- induced hypersensitivity are unknown. Injury to tissues can result in }sensitization} of nociceptors, resulting in enhanced response to noxious and normally non-noxious stimuli (i.e., hyperalgesia and allodynia, respectively). We hypothesize that opiate-induced hyperalgesia and allodynia may result from sensitization of nociceptors. Importantly, we hypothesize that sensitization of nociceptors by opiates can occur in the absence of tissue injury. Two specific questions are addressed by the experiments proposed in this application: 1) can opiates induce nociceptor sensitization without tissue injury? 2) is opiate-induced nociceptor sensitization the result, in part, of an NGF-dependent process? Behavioral, neurochemical, immunohistochemical and electrophysiological studies will test the hypothesis that opiates (a) act at opiate receptors to produce hypersensitivity and an increase in expression of NGF in peripheral tissues;(b) increase NGF-dependent phosphorylation of p38 MAPK (pp38 MAPK) in TrkA-positive cells, (c) increase NGF-dependent and pp38 MAPK-dependent trafficking of the TRPV1 channel to the periphery, (d) upregulate CGRP and substance P (SP) expression in TrkA-positive cells in an NGF-dependent, and pp38 MAPK-dependent fashion, and (e) produce NGF-, pp38 MAPK- and TRPV1-dependent hypersensitivity. PUBLIC HEALTH RELEVANCE: The consequences of opiate-induced neuroplasticity raise questions of whether unintended harm to patients might actually occur. Given the prevalent reliance on opiates for treatment of severe pain, understanding of the fundamental biological mechanisms associated with prolonged exposure to these drugs is essential. Additionally, mechanisms underlying possible nociceptor sensitization occurring in the absence of tissue injury may ultimately lead to insights into clinical conditions of prominent pain without apparent tissue injury including, for example fibromyalgia, IBS, CRPS-1 and perhaps migraine. The consequences of opiate-induced neuroplasticity raise questions of whether unintended harm to patients might actually occur. Given the prevalent reliance on opiates for treatment of severe pain, understanding of the fundamental biological mechanisms associated with prolonged exposure to these drugs is essential. Additionally, mechanisms underlying possible nociceptor sensitization occurring in the absence of tissue injury may ultimately lead to insights into clinical conditions of prominent pain without apparent tissue injury including, for example fibromyalgia, IBS, CRPS-1 and perhaps migraine.